Depressive disorders involve all major bodily functions, mood, and thoughts, affecting the ways in which an individual eats and sleeps, feel about themselves, and think. Without treatment, depression symptoms can last for weeks, months or years. Depression is the leading cause of disability in the United States. An increasing number of treatment options have become more available over the past two decades for individuals with major depression disorder. The clinical description of depression is complex, covering a broad range of symptoms that lack a unifying biological hypothesis. Depression has both genetic and environmental components, with linkage studies suggesting it is a polygenic disorder. Modern treatment for depression, which focuses exclusively on agents that modulate monoamine neurotransmission, began with a monoamine oxidase inhibitor (MAOI). MAOIs increase serotonin and norepinephrine concentrations in the brain by inhibiting the MAO enzyme. They are highly effective in treating depression but are used only scarcely owing to potentially dangerous drug interaction effects.
A second breakthrough in depression treatment came from chlorpromazine derivatives. Imipramine, one such derivative, was exceptionally effective in patients who had severe depression. Imipramine is a tricyclic antidepressant (TCA) that acts by inhibiting cellular reuptake mechanisms for norepinephrine and serotonin to increase activity within these G protein-coupled receptor (GPCR) families. Imipramine retains activity at GPCRs, but this activity contributes to unattractive side effects. Subsequently, structural analogs of diphenhydramine were discovered as novel antidepressants. The phenoxyphenylpropylamine was used to identify fluoxetine, the first selective serotonine reuptake inhibitor (SSRI). The remarkable success of fluoxetine as an antidepressant extended to the identification of other SSRIs including paroxetine, citalopram, fluvoxamine, and sertraline. SSRIs became a family of antidepressants considered to be the current standard of drug treatment. It is thought that one cause of depression is an inadequate amount of serotonin. SSRIs are said to work by preventing the reuptake of serotonin by the presynaptic neuron, thus maintaining higher levels of 5-HT in the synapse. These antidepressants typically have fewer adverse events and side effects than the tricyclics or the MAOIs, although such effects as drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, and decreased ability to function sexually may occur.
Although there are a number of treatments currently available, there are still clear opportunities for improvement of existing therapies. Much research has been focused to address unmet medical needs of currently available drug therapies: slow onset of action, inability to achieve full remission, difficulty of targeting significant populations of nonresponding patients, and minimalization of residual side effects including sexual dysfunction. Recent developments include serotonin and norepinephrine reuptake inhibitors (SNRIs), and norepinephrine and dopamine reuptake inhibitors (NDRIs), implying multiple neurotransmitter pathways in the spectrum of disorders that incorporate major depression [Pacher, P. et al., Curr. Med. Chem., 11, 925-943 (2004)]. It is the hope that drugs acting by newer mechanisms will meet some, if not all, of these unmet needs.
Along the line, SARI (serotonin antagonist/reuptake inhibitor) drugs that block both the serotonin 5-HT2 receptors and the serotonin transporters have been developed. Typical examples are Bristol-Myers Squibb's nefazodone [DeBattista, C. et al., Biol. Psychiatry, 44, 341 (1998)], Yamanouchi's YM-992 [Hatanaka, K. et al., Neuropharmacology, 35(11), 1621 (1997)] and Lilly's LY367265 [Pullar, I. A. et al., Eur. J. Pharmacol., 407(1-2), 39 (2000)]:

These compounds demonstrated improved results in the treatment of central nervous system disorders, compared with either the serotonin 5-HT2 receptors or the selective serotonin reuptake inhibitors only, in clinical effects, side effects, reduction in drug action time, etc. (see [Avila, A. et al., J. Clin. Psychopharmacol., 23(5), 509 (2003)]). Nefazodone is most closely related to trazodone in terms of chemical structure (see [Temple, D. L, Jr. et al., U.S. Pat. No. 4,338,317]). Unlike most SSRIs, nefazodone is reported to have no negative effects on libido or sexual functioning. Nefazodone's claimed advantages over other antidepressants include reduced possibility of disturbed sleep or sexual dysfunction, and ability to treat some patients who did not respond to other antidepressant drugs (see [Greene, D. S. et al., Clin. Pharmacokinet., 33(4), 260 (1997)]). However, nefazodone is a potent inhibitor of the CYP3A4 isoenzyme both in vitro and in vivo (see [Kent, J. M., Lancet, 355, 911-918 (2000)]).
In the end, its sale was discontinued in 2003 in some countries, due to the small possibility of hepatic injury, which could lead to the need for a liver transplant, or even death. At 2004, Bristol-Myers Squibb withdrew nefazodone in the United States.
In this regard, there is an urgent medical need on the discovery of new drugs that act as a mode of nefazodone, but have better developability characteristics. This new class of antidepressants would significantly broaden the physician's and patient's choice.